Advanced Glycation End Products Stimulate Angiotensinogen Production in Renal Proximal Tubular Cells

Background: Elevated advanced glycation end products (AGE) in diabetes mellitus (DM) are implicated in the progression of DM-associated tissue injury, including diabetic nephropathy. The intrarenal renin-angiotensin system, in particular augmentation of angiotensinogen (AGT) in proximal tubular cells (PTC), plays a crucial role in the development of diabetic nephropathy. This study investigated hypothesis that AGE stimulates AGT production in PTC. Materials and Methods: Urinary AGT and AGE levels in streptozotocin-induced DM mice were measured by enzyme-linked immunosorbent assays. AGT expression and secretion were evaluated in cultured rat PTC receiving 0-200 mu g/ml AGE-BSA treatments for 24 hours. Furthermore, intracellular signaling pathways activated by AGE were elucidated. Results: DM mice exhibited greater urinary AGT and AGE levels compared to control mice (AGT: 21.6 +/- 5.5 ng/day vs. 190.1 +/- 57.8 ng/day, AGE: 139.1 +/- 21.6 mu g/day vs. 332.8 +/- 102.7 mu g/day). In cultured PTC, treatment with AGE-BSA enhanced AGT mRNA expression (3.43 +/- 0.11-fold compared to control), intracellular AGT protein levels (3.60 +/- 0.38-fold), and secreted AGT levels (2.11 +/- 0.18-fold). On the other hand, AGT levels were not altered in PTC receiving nonglycated BSA. Recombinant soluble AGE receptor, which competes with endogenous AGE receptor, diminished the AGE-induced AGT upregulation, suggesting that AGE-BSA stimulates AGT expression via activation of the AGE receptor. Enhanced phosphorylation of ERK1/2 and c-Jun, but not p38 MAP kinase, were observed in AGE-BSA-treated PTC. AGE-induced AGT augmentation was attenuated by an ERK inhibitor. Conclusions: The findings indicate that AGE enhances proximal tubular AGT expression via ERK1/2, which can exacerbate the development of diabetic related kidney injury.